Plenary Session 3: Molecular Epidemiology and Tobacco "Molecular genetics of tobacco addiction", presented by Caryn E. Lerman, University of Pennsylvania Cancer Center, Philadelphia, PA. "Abundant data from animal studies and human twin studies have established that smoking behavior is, in part, heritable." "Human uptake and metabolism of tobacco carcinogens", presented by Stephen S. Hecht et al, University of Minnesota Cancer Center, Minneapolis, MN. "Carcinogens form the link between nicotine addiction and tobacco-related cancer. Over 60 carcinogens are present in tobacco smoke." "The constant barrage of DNA damage resulting from exposure to tobacco carcinogens is completely consistent with our current understanding of cancer as a consequence of multiple genetic changes. Specific biomarkers which allow quantitation of human carcinogen uptake and DNA adduct formation are now available for a variety of tobacco carcinogens." "Susceptibility to tobacco carcinogenesis", presented by Frederica P. Perera, Columbia University School of Public Health. "A major stumbling block in cancer prevention has been the lack of "early warning systems" to identify risk factors and subgroups at greatest risk. Molecular epidemiology was conceived as a preventive approach, to provide the molecular basis for intervention. Tobacco smoking is the leading cause of human cancer and is also a model carcinogen for the validation of biomarkers of risk, applicable to other environmental exposures." "...we have recently completed a placebo-controlled randomized, double-blind clinical trial involving 300 male and female smokers who were treated with antioxidant micronutrients (400 IU alpha-tocopherol; 500 mg vitamin C) or placebo over a fifteen month period. Among females, there was a significant effect of treatment on carcinogen-DNA adducts... Taken together, these research results have implications for risk assessment and public policy." "Expression of the gastrin-releasing peptide receptor by human airway cells:A field effect related to risk for lung cancer", presented by Jill M. Siegfried, University of Pittsburgh, Pittsburgh, PA. "These results suggest that expression of GRPR may be associated with underlying risk factor for lung obstruction and lung cancers and contribute to lung carcinogenesis. Expression of GRPR may also promote the carcinogenic effects of tobacco smoke." Plenary Session 4: Molecular Basis of Cancer Prevention/Delay "The retinoid/head and neck model and cancer delay", presented by Scott M. Lippman, UT M.D. Anderson Cancer Center, Houston, TX. "Cancer delay plays a major role in cancer chemoprevention. Retinoids in head and neck carcinogenesis are an excellent model of the molecular basis of cancer delay and provide its clinical proof of principle. Several trials involving retinoids and interferon in head-and-neck intraepithelial neoplasia (IEN) suggest that without a molecular complete response, cancer is being delayed rather than completely prevented. Single-agent 13-cis-retinoic acid produced phenotypic responses but did not eliminate p53 mutated clones. Prolonged 13-cis-retinoic acid therapy delayed IEN progression, although lesions became resistant to the retinoid over time, and lesion progression or drug resistance, was associated with persistent genotypic alterations and cancer development. These data suggest that cancer delay could result from prolonging the interval between critical genetic events in the multistep process. Combined retinoic acid-interferon therapy eradicated some clones; others persisted, despite complete phenotypic reversion, and probably retained the capacity to progress into phenotypically apparent lesions. The combination results suggest that eradicating premalignant clones also can achieve cancer delay. A major mechanism of cancer delay appears to involve detouring multistep carcinogenesis down alternative pathways. Well illustrated by translational studies in head and neck prevention, this detour concept is highly relevant to preventive molecular-targeting approaches." "It may be possible to enhance cancer delay through combinations of molecular-targeting agents (e.g., nonsteroidal anti-inflammatory drugs plus retinoic acid) that produce detours at multiple critical molecular junctures within multistep carcinogenesis." Ann's NOTE: It has been stated many times that 13-cis, all-trans and other retinoids are very toxic to the liver and other systems. Yet in a private discussion with a noted vitamin A researcher, I asked about this. He told me that vitamin A itself is less toxic than these retinoids. I asked why it was not used directly instead of the other forms? No real answer. His work has confirmed that there is minimal to no toxicity with up to 100,000 IU daily in human subjects. I personally took 300,000 IU daily for a week followed by 150-100,000 IU daily for 14 months, stopping every 8 weeks for 2 weeks due to a (possibly misplaced) fear of toxicity. I also had blood drawn every five weeks to make sure there was no liver toxicity. In my case, the result was the shrinking of a chest wall tumor. (more on this in the 'Ann's Bio' section on this site). "Molecular modulation of the tamoxifen-estrogen receptor (ER) complex", presented by V. Craig Jordan, Northwestern University Medical School, Chicago, IL. My notes indicate that although Tamoxifen lingers in the body for 4-6 weeks, Raloxifene "rapidly" clears in a few days. I asked about the connection seen in animal species (2 different ones as discussed at the 2001 National Breast Cancer Coalition's annual meeting) and ovarian cancer risk with Raloxifene but was not given a satisfactory answer. Advocates need to remember that the "endometrial cancer (adenocarcinoma) was not seen for more than ten years and sarcomas not until just a few years ago. Therefore dismissing the possibility of an ovarian 'connection' is premature. And, unfortunately for women diagnosed with breast cancer, risk of ovarian cancer is already higher. I wonder how long it would take to notice an increased risk? "Polyunsaturated fatty acid metabolism and colon cancer chemoprevention", presented by Imad Shureiqi, UT M.D. Anderson Cancer Center, Houston, TX. "The oxidative metabolism of omega-6 polyunsaturated fatty acid (PUFA) has been linked to tumorigenesis in animal models. The lipoxygenases (LOXs) and cyclooxygenases (COXs) are two enzyme groups that mediate the oxidative metabolism of linoleic and arachidonic acids in forming an array of biologically active metabolites, such as hydroxyeicosatetraenoic acids (HETEs), prostaglandins (PGs), and hydroxyoctadecadienoic acids (HODEs). The enzyme COX-2 is overexpressed in human cancers and has been linked to tumorigenesis. Initially, COX-2 was considered to be the major, if not the only, link between PUFA metabolism and colorectal carcinogenesis through the formation of PGE-2. It is now understood that other PUFA metabolic pathways beside COX-2 production of PGE-2 are involved. The LOXs convert arachidonic, linoleic, and other polyunsaturated fatty acids into biologically active metabolites that influence cell signaling, proliferation, and apoptosis." "Understanding the differential roles for PUFA oxidative metabolic pathways will enhance our ability to develop better molecularly targeted interventions to modulate PUFA oxidative metabolism for the chemoprevention of colon and other cancers." My notes indicate: Omega 3 inhibits tumorigenesis while Omega 6 enhances it. Sulindac sulfide (a drug) inhibits colon cancer without reducing prostaglandin formation. NSAIDs induce apoptosis (programmed cell death) independently of COX-2 and anti-inflammatories inhibit cancer growth but how is unknown. (Science 2001 article). "Targeting UV-induced signaling pathways for skin cancer chemoprevention", presented by G. Tim Bowden, University of Arizona, Tucson, AZ. "The incidence of skin cancer has been rising in recent years with significant effects on public health. Primary prevention has proven inadequate in impacting the incidence of skin cancer, thus stimulating the development of chemoprevention strategies. Both UVA and UVB are responsible for sunlight-induced cancers of the skin and have activity in initiating, promoting and progressing the development of squamous cell carcinomas (SCC). " "Epigallocatechin gallate (EGCG), a catechin from green tea was found to block UVB induced c-fos expression through a block in p38 MAP kinase activation. EGCG has been shown to inhibit UVB induced mouse skin carcinogenesis. Nordihydroguariaretic acid (NDGA), a polyphenolic compound from cresote bush, was found to inhibit UVB induced c-fos expression and AP-1 transactivation by inhibiting the PI-3 kinase pathway. NDGA has been shown to inhibit chemical carcinogenesis in mouse skin and is being tested for its activity in inhibiting UVB mouse skin carcinogenesis." My notes indicate that Dr. Bowden stated that 5 minutes of sun exposure in an Arizona summer was an overdose of UV rays. Skin cancer progresses from benign papilloma formations to squamous cell cancer and could progress further. Topical EGCG inhibits. NDGA also has implications for bowel and mammary cancers in mice. It may be an effective agent for secondary prevention of skin cancer. Other natural substances being explored include: vitamin A (retinol) which has had a phase III trial already; DFMO which has had a phase IIb trial; vitamin E topical (acetate-free), and perillyl alcohol (lavender-based). Acetate is apparently a promoter in skin cancer. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.